CD4+ T cell calibration of antigen-presenting cells optimizes antiviral CD8+ T cell immunity

Antiviral CD8+ T cell immunity depends on the integration of various contextual cues, but how antigen-presenting cells (APCs) consolidate these signals for decoding by T cells remains unclear. Here, we describe gradual interferon-a/interferon-ß (IFNa/ß)-induced transcriptional adaptations that endow APCs with the capacity to rapidly activate the transcriptional regulators p65, IRF1 and FOS after CD4+ T cell-mediated CD40 stimulation. While these responses operate through broadly used signaling components, they induce a unique set of co-stimulatory molecules and soluble mediators that cannot be elicited by IFNa/ß or CD40 alone. This response is critical for the acquisition of antiviral CD8+ T cell effector function, and its activity in APCs from individuals infected with severe acute respiratory syndrome coronavirus 2 correlates with milder disease. These observations uncover a sequential integration process whereby APCs rely on CD4+ T cells to select the innate circuits that guide antiviral CD8+ T cell responses. Overall design: Examination of IFN-aA and a-CD40 signaling in BM-derived cDC1